Project Summary/Abstract The aging brain is increasingly susceptible to cognitive decline and dementia. Alzheimer?s disease (AD), a main form of dementia, is an extreme, pathological manifestation of brain aging. However, the etiology and pathogenesis of AD are not well understood, causing the dearth of effective treatments. Mounting evidence has implicated epigenetic changes, such as DNA methylation and histone acetylation, in neuronal aging and degeneration, raising the hypothesis that resetting these epigenetic changes and restoring a youthful epigenome may increase neuroplasticity and forestall disease. We have recently discovered that epigenetic reprogramming by coexpression of three Yamanaka factors, Oct4, Sox2, and Klf4 (OSK), can induce axon regeneration in retinal ganglion cells (RGCs), a type of central nervous system (CNS) neuron, after acute injury. Furthermore, OSK expression in RGCs of old mice reversed aging-associated transcriptome changes, reset the DNA methylation age of the cells, and restored vision to a level similar to young mice, suggesting neuronal rejuvenation. Importantly, cell cycle, cell identity, and intrinsic electrophysiological properties of postmitotic neurons were not affected by OSK reprogramming. In this proposal, I seek to identify the epigenetic mechanisms that underlie OSK-mediated axon regeneration (Aim 1), determine whether epigenetic reprogramming in brain neurons reverses age-associated cognitive decline and epigenomic changes (Aim 2), and investigate the role of epigenetic changes in the progression of AD (Aim 3). A new mouse model that allows temporal control of epigenetic reprogramming in the forebrain neurons will be used to evaluate the therapeutic effect of epigenetic reprogramming in AD through a combination of molecular, physiological, behavioral, and histological techniques. Based on our preliminary results, I hypothesize that reversal of the aging epigenome in CNS neurons will improve neuronal plasticity and restore cognitive function that are impaired due to aging and Alzheimer?s disease. This work will provide novel insights into the etiology of AD, identify the epigenetic links between aging and AD, and may reveal a new realm of therapeutics. Aims 1 and 2 will be performed predominantly during the K99 phase under the mentorship of Dr. David Sinclair, a leader in aging and epigenetics; Dr. Edward Boyden, a world- renowned neuroscientist; and Dr. Steve Horvath, an expert in DNA methylation and aging. Aim 3 will be performed predominantly during the R00 phase. The mentorship program and proposed research will allow me to gain rigorous scientific training in neuroscience and bioinformatics, specializing in neurodegeneration, neurophysiology, and genome-wide epigenetic analysis. In addition, in conducting the K99 phase at Harvard Medical School, my work will benefit from the highly collaborative research environment, state-of-the-art technologies and facilities, and world-renowned experts available for collaboration and consultation. The award will enable an in-depth career development plan for me to expand the scope of my research and launch an independent research program focused on studying epigenetic mechanisms of neuronal aging and degeneration.